The compound 4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[(4-trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide (CAS#254964-60-8, herein below also referred to as ABR-215050) has shown efficacy in animal experiments relevant for cancer (1). It also has been shown that ABR-215050 is capable of inhibiting prostate tumor growth via a mechanism involving an anti-angiogenic response (2); a clear anti-tumor response has been achieved in a number of in vivo tumor models using human prostate cancer cell lines (3). This has encouraged further trials on the compound and efficacy in the treatment of human cancer has been shown in a phase 2 clinical trial (4).
In a recent, randomized placebo-controlled double blind phase II clinical study of ABR-215050 in patients with asymptomatic metastatic castrate-resistant prostate cancer, a difference was shown in the number of patients with disease progression at six months. Indeed, the results showed that the fraction of patients with disease progression during the six month period was 31% for patients treated with ABR-215050, compared to 66% for placebo treated patients (p<0.0001). The median progression free survival was 7.6 months for the group treated with ABR-215050, compared to 3.2 months for the placebo group (p=0.0009). ABR-215050 treatment also had an effect on biomarkers relevant for prostate cancer progression and was generally well tolerated.
In vivo animal experiments further have shown that ABR-215050 also has an efficacy in the treatment of autoimmune diseases. Thus, an in vivo animal experimental study has shown efficacy of the compound in the treatment of rheumatoid arthritis (5), and another one has shown its efficacy in the treatment of multiple sclerosis (6).
Deuterium (2H or D) is a stable and non-radioactive isotope of hydrogen which has approximately twice the mass of protium (1H or H), the by far most common isotope of hydrogen. Deuteration of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles has been disclosed previously with some classes of drugs. For example, it has been disclosed (7) that various deuteration patterns can be used to (a) reduce or eliminate unwanted metabolites, (b) increase the half-life of the parent drug, (c) decrease the number of doses needed to achieve a desired effect, (d) decrease the amount of a dose needed to achieve a desired effect, (e) increase the formation of active metabolites, if any are formed, (f) decrease the production of deleterious metabolites in specific tissues, and/or (g) create a more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy be intentional or not. In (7), therefore, deuteration of laquinimod is disclosed and it is stated that the deuteration approach has the strong potential to slow the metabolism of laquinimod